The present invention relates to the new compounds, piperidinyl- or piperazinyl-substituted-1,2,3,4-tetrahydronaphthalene derivatives as (R)-enantiomers, (S)-enantiomers or racemates in the form of a free base or pharmaceutically acceptable salts thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.
An object of the invention is to provide compounds for therapeutic use, especially compounds having a selective effect at a subgroup of 5-hydroxy-tryptamine receptors, designated the 5-HT1D-receptor in mammals including man.
It is also an object of the invention to provide compounds with a therapeutic effect after oral administration.
Different classes of piperazinyl substituted benzanilide derivatives as 5-HT1D antagonists are disclosed in inter alia EP 533266, EP 533267, EP 533268, GB 2273930 and WO 95/11243.
WO 94/13659 discloses an extremely broad class of fused benzo compounds having a para substituted piperidinyl or piperazinyl radical in the aromatic ring. Said class of compounds is stated to bind to the 5-HT1A receptor.
WO 94/21619 discloses a fully aromatic naphthalene ring system which may be substituted with a piperidinyl or piperazinyl group, said compounds are also stated to be potent serotonin (5HT1) agonists and antagonists.
EP 402923 discloses 2-aminoalkyl or alkylenaromatic substituted 1,2,3,4-tetrahydronaphthalene derivatives having a further nitrogen substitution in the 5 position in the tetraline ring. Said compounds act as dopamine agonists.
Various central nervous system disorders such as depression, anxiety, etc. appear to involve the disturbance of the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine (5-HT), the latter also known as serotonin. The drugs most frequently used in the treatment of depression are believed to act by improving the neurotransmission of either or both of these physiological agonists. It appears that the enhancement of 5-HT neurotransmission primarily affects the depressed mood and anxiety, whereas the enhancement of noradrenaline neurotransmission affects the retardation symptoms occurring in depressed patients. The invention concerns compounds which have an effect on 5-HT neurotransmission.
Serotonin, or 5-HT, activity is thought to be involved in many different types of psychiatric disorders. For instance it is thought that an increase in 5-HT activity is associated with anxiety, while a decrease in 5-HT release has been associated with depression. Serotonin has in addition been implicated in such diverse conditions as eating disorders, gastrointestinal disorders, cardiovascular regulation and sexual behavior.
The 5-HT Receptors
The various effects of 5-HT may be related to the fact that serotoninergic neurons stimulate the secretion of several hormones, e.g. cortisol, prolactin, xcex2-endorphin, vasopressin and others. The secretion of each of these other hormones appears to be regulated on a specific basis by several different 5-HT (serotonin) receptor subtypes. With the aid of molecular biology techniques, to date these receptors have been classified as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-ht5, 5-ht6 and 5-ht7 with the 5-HT1 receptor further divided into the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F subtypes. Each receptor subtype is involved in a different serotonin function and has different properties.
Regulation of the 5-HT Transmission
The release of 5-HT at the nerve terminals is feedback-regulated by two different subtypes of 5-HT receptors. Inhibitory 5-HT1A autoreceptors are located on the cell bodies in the raphxc3xa9 nuclei which upon stimulation by 5-HT decrease the impulse propagation in the 5-HT neurons and thereby reduce the 5-HT release at the nerve terminals. Another subtype of inhibitory 5-HT receptors is located on the 5-HT nerve terminals, the 5-HT1D receptors (in rodents the 5-HT1B receptors) which regulate the synaptic concentration of 5-HT by controlling the amount of 5-HT that is released. An antagonist of these terminal autoreceptors thus increases the amount of 5-HT released by nerve impulses, as has been shown in both in vitro and in vivo experiments.
The use of an antagonist of the terminal 5-HT1D autoreceptor will accordingly increase the synaptic 5-HT concentration and enhance the transmission in the 5-HT system. The antagonist would thus produce an antidepressant effect making it useful as a medication for depression.
Other localizations of 5-HT1D receptor subtype also exist. A large part of these receptors appear to be located on nerve terminals of other neuronal systems (so called heteroreceptors). Since the 5-HT1D receptor mediates inhibitory responses, an antagonist of this receptor subtype might also increase the release of other neurotransmitters than 5-HT.
Compounds having 5-HT1D activity may according to well known and recognized pharmacological tests be divided into full agonists, partial agonists and antagonists.
The primary object of the present invention is to provide compounds having a selective effect at the 5-HT1D receptor, preferably antagonistic properties, as well as having a good bioavailability. The effect on the other receptors chosen from, for example, the 5-HT1A, 5-HT2A, D1, D2A, D3, xcex11 and xcex12 receptor has been investigated.
Accordingly, the present invention provides compounds of the formula I 
wherein
X is N or CH;
Y is NR2CH2, CH2xe2x80x94NR2, NR2xe2x80x94CO, COxe2x80x94NR2 or NR2SO2;
R1 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R2 is H or C1-C6 alkyl;
R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl,
where aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R4 and/or R5;
R4 is H, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, CN, CF3, OH, C1-C6 alkoxy, NR6R7, OCF3, SO3CH3, SO3CF3, SO2NR6R7, phenyl, phenyl-C1-C6 alkyl, phenoxy, C1-C6 alkyl, phenyl, C1-C6 alkyl-heterocyclic ring containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO2, an optionally substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO2, wherein the optional substituent(s) is(are) selected from C1-C6 alkyl, C3-C6 cycloalkyl and phenyl-C1-C6 alkyl; or COR8;
R5 is H, OH, CF3, OCF3, halogen, C1-C6 alkyl or C1-C6 alkoxy,
R6 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R7 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R8 is C1-C6 alkyl, C3-C6 cycloalkyl, CF3, NR6R7, phenyl, or a heterocyclic ring containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO2;
n is 0-4;
as (R)-enantiomer, (S)-enantiomer or a racemate in the form of the free base or a pharmaceutically acceptable salt or hydrate thereof which possesses a high selective effect at the 5-HT1D receptor and also shows sufficient bioavailability after oral administration.
In the present context C1-C6 alkyl may be straight or branched. C1-C6 alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl.
In the present context C1-C6 alkoxy may be straight or branched. C1-C6 alkoxy may be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy, neo-pentyloxy, n-hexyloxy or i-hexyloxy.
In the present context C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclohexyl.
In the present context halogen may be fluoro, chloro, bromo or iodo.
In the present context the heteroaromatic ring containing one or two heteroatoms selected from N, O and S preferably is a 5- or 6-membered heteroaromatic ring and may be furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl. The heteroaromatic ring can be either substituted or unsubstituted.
In the present context the heterocyclic ring containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO2 may optionally contain a carbonyl function and is preferably a 5-, 6- or 7-membered heterocyclic ring and may be imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidinyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, preferably piperidino, 1-piperazinyl, morpholino, thiomorpholino and 4-piperidon-1-yl.
A preferred embodiment of the invention relates to compounds of formula I wherein the piperidinyl or piperazinyl is in the 5 position. The most preferred embodiment of the invention relates to compounds of formula I wherein the piperidinyl or piperazinyl is in the 8 position. Another possibility is that the piperidinyl or piperazinyl is in the 6 or 7 position.
Another preferred embodiment of the invention relates to compounds of formula I wherein Y is NHCO or CONH i.e. amides. Of those compounds, the compounds wherein R3 is unsubstituted phenyl, or mono- or di-substituted phenyl, and especially ortho-, meta- or para-substituted phenyl, and particularly those wherein the substituent R4 is phenyl, phenyl-C1-C6 alkyl, cyclohexyl, piperidino, 1-piperazinyl, morpholino, CF3, 4-piperidon-1-yl, n-butoxy or COR8 wherein R8 is phenyl, cyclohexyl, 4-piperidon-1-yl, 1-piperazinyl, morpholino, CF3, piperidino or NR6R7, are preferred.
Examples of suitable combinations of substituents are:
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidinyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidinyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidinyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)-phenyl;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholinyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholinyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidinyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholinyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholinyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidinyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholinyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidinyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)-phenyl;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidinyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidinyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholinyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl R4 is piperidinyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholinyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is morpholinyl;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholinyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidinyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is COR8, R8 is NR6R7, R6R7CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholinyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholinyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is morpholinyl;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholinyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidinyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidinyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholinyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is cyclohexyl;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl.
Preferred compounds are:
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-(trifluoroacetyl)benzamide,
(R)-N-[8-(1-Methylpiperidin-4-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-piperidinobenzamide,
(S)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-N,N-diethylaminobenzamide,
(R)-N-[8-(4-Propylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-ethylbenzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinocarbonylbenzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzarnide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-butoxybenzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-(1H-pyrrol-1-yl)benzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-3-methyl-4-morpholinobenzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-(4-ethylphenyl)benzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-trifluoromethylbenzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-(N,N-dipropylaminosulphony)benzamide,
(R)-N-[8-(4-Ethylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide,
(R)-N-[8-(1-Methylpiperidin-4-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-trifluoromethylbenzamide,
(R)-N-[8-(1-Methylpiperidin-4-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-butoxybenzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-cyclohexylbenzamide,
(R)-N-[8-(Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-(4-piperidon-1-yl)benzamide,
(R)-N-8-(Piperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide,
N-(4-Morpholinocarbonylphenyl)-8-[4-(methylpiperazin-1-yl)]-1,2,3,4-tetrahydronaphthalene-2-carboxamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-(4-morpholinomethyl)benzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-(N,N-dimethylaminocarbonyl)benzamide,
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinocarbonylbenzamide or
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-thiomorpholinobenzamide
Another preferred group of compounds is:
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-2-methylbenzamide
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-cyanobenzamide
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-fluorobenzamide
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-(4-hydroxyphenyl)benzamide and
(R)-N-[8-(4-Methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-3-phenoxybenzamide
The compounds of the present invention are in the form of the racemate or the (R)- or (S)-enantiomer in the form of a free base or a pharmaceutically acceptable salt or hydrate thereof. Compounds in the form of the (R)-enantiomer are preferred ones.
Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, dibenzoyltartaric, diacetyltartaric, palmoic, ethanedisulfonic, sulfamic, succinic, propionic, glycolic, malic, gluconic, pyruvic, phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxybenzoic, 3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic, naphthalenesulfonic, ascorbic, cyclohexylsulfamic, fumaric, maleic and benzoic acids. These salts are readily prepared by methods known in the art.
Pharmaceutical Formulations
In a second aspect the present invention provides a pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound of formula I as an enantiomer or a racemate in the form of a free base or a pharmaceutically acceptable salt or hydrate thereof, optionally in association with diluents, excipients or inert carriers.
According to the present invention the compound of the invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical formulations comprising the active ingredient either as a free base or a pharmaceutically acceptable non-toxic acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in a pharmaceutically acceptable dosage form. The dosage form may be a solid, semisolid or liquid preparation. Usually the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.
To produce pharmaceutical formulations containing the compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidone, or a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatin, talcum, titanium dioxide, and the like. Alternatively, the tablet can be coated with a polymer known to the person skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish among tablets containing different active substances or different amounts of the active compound.
For the preparation of soft gelatin capsules, the active substance may be admixed with e.g. a vegetable oil or poly-ethylene glycol. Hard gelatin capsules may contain granules of the active substance using either the above mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Also liquid or semisolid forms of the drug can be filled into hard gelatin capsules.
Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in a mixture with a neutral fatty base, or in the form of gelatin rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil. Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.1% to about 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharin and carboxymethyl-cellulose as thickening agent or other excipients known to the person skilled in the art.
Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from about 0.1% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
Suitable daily doses of the compound of the invention in therapeutical treatment of humans are about 0.01-100 mg/kg body weight for peroral administration and 0.001-100 mg/kg body weight for parenteral administration.
Medical and Pharmaceutical Use
In a further aspect the present invention provides the use of the compounds of formula I in therapy as 5-HTID antagonists, partial agonists or full agonists,preferably as antagonists and the use in the treatment of 5-hydroxytryptamine mediated disorders. Examples of such disorders are disorders in the CNS such as mood disorders (depression, major depressive episodes, dysthymia, seasonal affective disorder, depressive phases of bipolar disorder), anxiety disorders (obsessive compulsive disorder, panic disorder with/without agoraphobia, social phobia, specific phobia, generalized anxiety disorder, posttraumatic stress disorder), personality disorders (disorders of impulse control, trichotellomania), obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders (age associated memory impairment, presenile and senile dementia), pathological aggression, schizophrenia, endocrine disorders (e g hyperprolactinaemia), stroke, dyskinesia, Parkinson""s disease, thermoregulatory disorders, pain and hypertension. Other examples of 5-hydroxytryptamine mediated disorders are urinary incontinence, vasospasm and growth control of tumors (e g lung carcinoma).
Methods of Preparation
The present invention also relates to processes for preparing the compounds of formula (I). Throughout the following description of such processes it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d T. W. Greene, Wiley-Interscience, New York, 1991.
The below described methods for substitution in the 8-position are also applicable to substitution in the 5-position.
Methods of Preparation of Intermediates
1.
(i) Benzylation of the compound of the formula (II), either as a racemate or as an enantiomer, 
to obtain a compound of formula (III) may be carried out by reaction with a suitable benzylation agent e.g. a benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol e.g. benzylmesylate or benzyltosylate. The reaction may be carried out using a salt or the base of compound (II) in a suitable solvent e.g. N,N-dimethylformamide, acetone or acetonitrile with a suitable base e.g. NaOH, NaHCO3, K2CO3 or a trialkylamine such as triethylamine at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of a suitable catalyst e.g. potassium iodide or sodium iodide, may increase the speed of the reaction. The nitrogen in compound (II) may also be protected by reductive alkylation with an arylaldehyde in the presence of a reductive agent such as sodium cyanoborohydride, sodium borohydride or catalytically with H2 and a suitable catalyst containing palladium, platinium, rhodium or nickel in a suitable solvent e.g. tetrahydrofuran, dioxane, methanol or ethanol. A proton donor such as p-toluenesulfonic acid can be used to catalyze the formation of the imine/enarnine, and adjustment of pH to slightly acidic by an appropriate acid such as acetic acid may speed up the reaction, resulting in compound (III).
(ii) Demethylation of the compound of formula (III) 
to obtain a compound of formula (IV) may be carried out by treating the compound with an acidic reagent such as aqueous HBr, HI, HBr/CH3COOH, BBr3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as CH3C6H4Sxe2x88x92 or C2H5Sxe2x88x92 in a suitable solvent. Suitable solvents may be methylene chloride or chloroform and the reaction may occur between xe2x88x9278xc2x0 C. and +60xc2x0 C.
(iii) Conversion of the compound of formula (IV) to a compound of formula (V) 
may be carried out by the reaction with a compound of formula (VI) 
where X stands for a leaving group, e.g. a halogen such as chlorine, bromine or iodine or an alkane- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and Ra and Rb are hydrogen or a lower alkyl group e.g. methyl. The process may be carried out with a salt of the compound of formula (IV) obtained by reaction with a base such as K2CO3, Na2CO3, KOH, NaOH, BuLi or NaH. The reaction may be conducted in a suitable solvent e.g. an aprotic solvent such as dioxane, N,N-dimethylformamide, tetrahydrofuran, toluene, benzene or petroleum ether and the reaction may occur between +20xc2x0 C. and +150xc2x0 C.
(iv) Rearrangement of a compound of formula (V) to a compound of formula (VII) 
may be carried out in a suitable solvent e.g. aprotic solvent such as N,N dimethylformamide, dioxane, 1,1,3,3-tetramethylurea, tetrahydrofuran or hexamethylphosphoric triamide with a suitable base e.g. K2CO3, KOH, potassium tert-butoxide or NaH at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of a cosolvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone or hexamethylphosphoric triamide in appropriate concentration in the solvent may increase the speed of the reaction.
(v) Hydrolysis of a compound of formula (VII) to a compound (VIII) may be carried out under acidic conditions using acids such as H2SO4, HCl or HBr in a suitable solvent e.g. H2O, ethanol, methanol or mixtures thereof and the reaction may occur between +20xc2x0 C. and +100xc2x0 C. or under basic conditions using bases such as NaOH or KOH in a suitable solvent e.g. H2O, ethanol, methanol or mixtures thereof and the reaction may occur between +20xc2x0 C. and +100xc2x0 C.
(vi) Conversion of compound of formula (VIII) to a compound of formula (IX) 
may be carried out by
a) reaction with a compound of formula (X) 
xe2x80x83where R1 is C1-C6 alkyl or C3-C6 cycloalkyl. The process may be carried out in a suitable solvent e.g. an aprotic/anhydrous solvent such as tetrahydrofuran or N,N-dimethylformamide in the presence of coupling reagent such as N,Nxe2x80x2-carbonyldiimidazole and the reaction may occur between +20xc2x0 C. and +130xc2x0 C. The reaction is followed by the reduction of the imide with a suitable reducing agent e.g. LiAlH4 in a suitable solvent e.g. diethyl ether or tetrahydrofuran at a temperature between +20xc2x0 C. and reflux, or
b) by reaction with a compound of formula (XI) 
xe2x80x83where X stands for a leaving group, e.g. a halogen such as chlorine or bromine or an alkane- or arenesulfonyloxy group such as p-toluenesulfonyloxy group and R1 is C1-C6-alkyl or C3-C6 cycloalkyl. The process may be carried out in a suitable solvent such as ethanol, buthanol, N,N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base e.g. K2CO3, NaHCO3 or KOH and the reaction may occur between +20xc2x0 C. and +150xc2x0 C.
Alternatively, a compound of formula (IX) may be prepared by,
(vii) Benzylation of the compound of the formula (XV), either as a racemate or as an enantiomer, 
where Rc stands for a halogen such as bromine, iodine or a trifluoromethylsulfonyloxy group, to obtain a compound of formula (XVI) by reaction with a suitable benzylating agent e.g. benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol e.g. benzylmesylate or benzyltosylate. The reaction may be carried out by using the salt or the base of compound (XV) in a suitable solvent e.g. N,N-dimethylformamide, acetone or acetonitrile with a suitable base e.g. NaOH, NaHCO3, K2CO3 or a trialkylamine such as triethylamine at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of suitable catalyst e.g. alkali metal iodide such as potassium iodide or sodium iodide may increase the speed of the reaction.
The nitrogen in compound (XV) may also be protected by reductive alkylation with an arylaldehyde in the presence of a reductive agent such as sodium cyanoborohydride, sodium borohydride or catalytically with H2 and a suitable catalyst containing palladium, platinium, rhodium or nickel in a suitable solvent e.g. tetrahydrofuran, dioxane, methanol or ethanol. A proton donor such as p-toluenesulfonic acid can be used to catalyze the formation of the imine/enamine and adjustment of pH to slightly acidic by an appropriate acid such as acetic acid may speed up the reaction, resulting in compound (XVI). 
(viii) Conversion of the compound of formula (XVI) to a compound of formula (IX), where R1 is C1-C6 alkyl or C3-C6 cycloalkyl, may be carried out by reaction with a compound of formula (XVII). 
The process may be carried out in a suitable solvent e.g. an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N,N-dimethylforinamide with a suitable base such as sodium tert-butoxide or lithium bis(trimethylsilyl)amide in the presence of a suitable palladium catalyst such as PdX2, L2Pd(0) or L2PdX2 where X stands for a halogen such as chlorine or bromine and L stands for a suitable ligand such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, triphenylarsine or dibenzylidenacetone and with or without an addition of a ligand Lxe2x80x2 such as triphenylphosphine, tri-o-tolylphosphine, trifurylphdsphine, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthalene (either as a racemate or as an enantiomer) or triphenylarsine and the reaction may occur at a temperature between +20xc2x0 C. and +150xc2x0 C., resulting in the compound of the formula (IX).
The conversion of (XVI) to (IX) can also proceed via the tranformation of (XVII) to an aminostannane or aminoborane using agents such as (N,N-diethylamino)tributyltin and tris(dimethylamino)borane in a suitable solvent e.g an aprotic solvent such as benzene, toluene, dioxan, tetrahydrofuran or N,N-dimethylformamide and then using similar conditions as described in the above description, resulting in the compound of the formula (IX).
Compound of formula (IX) may also be prepared by,
(ix) Alkylation of a compound of formula (XIII), wherein R1 is hydrogen, with a suitable alkylation reagent such as R1xe2x80x94L where L is a suitable leaving group e.g. a halogen such as chlorine, bromine or iodine or an alkane- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and R1 is C1-C6 alkyl. The reaction may be carried out in a suitable solvent such as N,N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran with a suitable base such as K2CO3, NaHCO3, NaOH or a trialkylamine such as triethylamine. The reaction may be conducted at a temperature between +20xc2x0 C. and +120xc2x0 C.
Alternatively,
(x) conversion of a compound of formula (XIII), wherein R1 is hydrogen, to a compound of formula (IX) may be carried out by reductive alkylation with a compound R1xe2x80x94CHO, where R1 is hydrogen or C1-C5 alkyl, or with a C3-C6 cyclic ketone, in the presence of a reductive agent such as sodium cyanoborohydride, sodium borohydride or catalytically with H2 and a suitable catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent e.g. tetrahydrofuran, dioxane, methanol or ethanol. A proton donor such as p-toluenesulfonic acid can be used to catalyze the formation of the imine/enamine and adjustment of pH to slightly acidic by an appropriate acid such as acetic acid may speed up the reaction, resulting in compound (IX).
(xi) In the case where R1 is methyl, conversion of a compound of formula (XIII) to a compound of formula (IX) may be carried out by 
a) conversion of the compound of formula (XIII) to a compound of formula (XLVI), where Re is C1-C6 alkyl, with a reagent such as an alkyl chioroformate e.g. ethyl chloroformate in a solvent such as methylene chloride, chloroform, dioxane or diethyl ether with a suitable base such as K2CO3, NaHCO3, NaOH or a trialkylamine such as triethylamine at a reaction temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C. followed by,
b) reduction of the compound of formula (XLVI) to a compound of formula (IX) with an appropriate reductive agent such as lithium aluminum hydride in a suitable solvent e.g. diethyl ether or tetrahydrofuran at a temperature between +20xc2x0 C. and reflux.
(xii) Conversion of the compound of formula (IX) to a compound of formula (XII) 
where R1 is C1-C6 alkyl or C3-C6 cycloalkyl may be carried out by
a) hydrogenation using a catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent e.g. acetic acid or ethanol and at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or
b) debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd/C and at a reaction temperature between +20xc2x0 C. and reflux. 
(xiii) In the case when R1 is hydrogen, conversion of compound of formula (VIII) to a compound of formula (XIII) may be carried out by reaction with a compound of formula (XI) where X stands for a leaving group, e.g. a halogen such as chlorine or bromine or an alkane- or arenesulfonyloxy group such as p-toluenesulfonyloxy group and R1 is hydrogen. The process may be carried out in a suitable solvent such as ethanol, butanol, N,N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base e.g. K2CO3, NaHCO3 or KOH and the reaction may occur between +20xc2x0 C. and +150xc2x0 C.
(xiv) Conversion of a compound of formula (XIII), where R1 is hydrogen, to a compound of formula (XIV), 
where Rd stands for a suitable protecting group, may be carried out by
a) hydrogenation using a catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent e.g. acetic acid or ethanol at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or
b) debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd/C at a reaction temperature between +20xc2x0 C. and reflux.
Said reaction is followed by the protection of the piperazine ring in a suitable solvent e.g. methylene chloride or chloroform with an appropriate protecting reagent e.g. di-tert-butyl dicarbonate with a suitable base e.g. triethylamine or K2CO3 and at a temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C., resulting in compound of formula (XIV).
Alternatively, a compound of formula (XIV) may be prepared by, 
(xv) Conversion of the compound of formula (XVI) to a compound of formula (XVIII), where Rd is a suitable protecting group such as a benzyl or tert-butyloxycarbonylgroup, may be carried out by the reaction with a compound of formula (XIX). 
The process may be carried out in a suitable solvent e.g. an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N,N-dimethylformamide with a suitable base such as sodium tert-butoxide or lithium bis(trimethylsilyl)amide in the presence of a suitable palladium catalyst such as PdX2, L2Pd(0) or L2PdX2 where X stands for a halogen such as chlorine or bromine and L stands for a suitable ligand such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, triphenylarsine or dibenzylidenacetone and with or without an addition of a ligand Lxe2x80x2 such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthalene (either as a racemate or as an enantiomer) or triphenylarsine and the reaction may occur at a temperature between +20xc2x0 C. and +150xc2x0 C., resulting in the compound of the formula (XVIII).
The conversion of (XVI) to (XVIII) can also proceed via the tranformation of (XIX) to an aminostannane or aminoborane using agents such as (N,N-diethylamino)tributyltin and tris(dimethylamino)borane in a suitable solvent e.g an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N,N-dimethylformamide and then using similar conditions as described in the above description, resulting in the compound of the formula (XVIII). 
(xvi) Conversion of the compound of formula (XVII) to a compound of formula (XX) may be carried out by removal of the protecting group Rd of the compound of formula (XVIII) by methods known in the art such as
a) hydrolysis of a tert-butyloxycarbonylgroup in a suitable solvent e.g. methylene chloride or chloroform with a suitable acid such as trifluoroacetic acid at a temperature between +20xc2x0 C. and +60xc2x0 C., followed by
b) cleavage of the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platinum or nickel, in a suitable solvent e.g. acetic acid or ethanol at a temperature between +20xc2x0 C. and +120xc2x0 C., or alternatively by,
c) debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd/C and at a reaction temperature between +20xc2x0 C. and reflux.
Said reaction is followed by the protection of the piperazine ring in a suitable solvent such as methylene chloride or chloroform with an appropriate protecting reagent e.g. di-tert-butyl dicarbonate with a suitable base such as triethylamine or K2CO3 at a temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C., resulting in in the compound of formula (XIV).
2.
(i) Halogenation of the compound of formula (XXI), either as a racemate or as an enantiomer 
to obtain a compound of formula (XXII) may be performed by aromatic electrophilic substitution using a suitable halogenation agent such as Br2, Cl2, I2, ICl, or SO2Cl2. The reaction may be carried out using the salt or the base of the compound (XXI) in an appropriate solvent e.g. acetic acid, HCl/ethanol or water with or without a suitable base e.g. an alkali metal acetate such as sodium acetate and at a reaction temperature between xe2x88x9220xc2x0 C. and room temperature. 
(ii) Benzylation of the compound of the formula (XXII), either as a racemate or as an enantiomer, to obtain a compound of the formula (XXIII) may be carried out by reaction with a suitable benzylation agent e.g. benzyl halide such as benzyl bromide or benzyl chloride. The reaction may be carried out using the salt or the base of compound (XXII) in a suitable solvent e.g. N,N-dimethylformamide, acetone or acetonitrile with a suitable base such as triethylamine, NaOH, NaHCO3 or K2CO3 at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of a suitable catalyst e.g. an alkali metal halide such as potassium iodide or sodium iodide may increase the speed of the reaction. The nitrogen in compound (XXII) may also be protected by reductive alkylation with an arylaldehyde in the presence of a reductive agent such as sodium cyanoborohydride, sodium borohydride or catalytically with H2 and a suitable catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent e.g. tetrahydrofuran, dioxane, methanol or ethanol. A proton donor such as p-toluenesulfonic acid can be used to catalyze the formation of the imine/enamine and adjustment of pH to slightly acidic by an appropriate acid such as acetic acid may speed up the reaction, resulting in compound (XXIII). 
iii) The conversion of the compound of the formula (XXIII) to the compound of the formula (XXIV), where R1 is C1-C6 alkyl or C3-C6 cycloalkyl, may be performed by a metal-halogen exchange, in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether using a suitable alkyl-lithium or metal e.g. butyllithium, lithium or magnesium turnings, followed by treatment with an appropriate piperidone such as N-methyl-4-piperidone and a subsequent suitable workup. The reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature. 
(iv) The compound of the (XXIV) may be reduced to the compound of the formula (XXV) by treatment with a suitable reducing agent such as sodium borohydride and a protonating agent such as CF3COOH, CF3SO3H or HCOOH in an appropriate solvent such as tetrahydrofuran or diethyl ether. The reaction may be performed at reaction temperature between 0xc2x0 C. and reflux. 
(v) Demethylation of the compound of the formula (XXV) to obtain a compound of formula (XXVI) may be performed by treating the compound with an acidic reagent such as aqueous HBr, HI, HBr/acetic acid, BBr3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as C2H5Sxe2x88x92 or CH3C6H4Sxe2x88x92 in a suitable solvent. Suitable solvents may be methylene chloride or chloroform and the reaction may occur between xe2x88x9278xc2x0 C. and +60xc2x0 C. 
(vi) Conversion of the compound of formula (XXVI) to a compound of formula (XXVII) may be carried out with a compound such as trifluoromethanesulfonic anhydride in a suitable solvent such as methylene chloride or carbon tetrachloride in the presence of a base such as 2,4,6-collidine, triethylamine or pyridine at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature. 
vii) Conversion of the compound of formula (XXVII) to a compound of formula (XXVIII) may be performed by
a) hydrogenation using a catalyst such as palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or
b) reaction in a suitable solvent such as methanol in the presence of ammonium formate and Pd/C at a reaction temperature between +20xc2x0 C. and reflux.
Alternatively, a compound of formula (XXVIII) may be prepared by, 
(viii) The conversion of a compound of the formula (XVI), where Rc is a halogen such as bromine, to a compound of the formula (XXIX), where R1 is C1-C6 alkyl or C3-C6 cycloalkyl. This may be performed by a metal-halogen exchange, in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether using a suitable alkyl-lithium or metal e.g. butyllithium, lithium or magnesium turnings, followed by treatment with appropriate piperidone such as N-methyl-4-piperidone and a subsequent suitable workup. The reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature. 
(ix) A compound of the formula (XXIX) may be reduced to a compound of the formula (XXX) by treatment with a suitable reducing agent such as sodium borohydride and a protonating agent such as CF3COOH, CF3SO3H or HCOOH in an appropriate solvent such as tetrahydrofuran or diethyl ether. The reaction may be performed at a reaction temperature between 0xc2x0 C. and reflux.
(x) Conversion of a compound of formula (XXX) to a compound of formula (XXVIII), where R1 is C1-C6 alkyl or C3-C6 cycloalkyl, may be performed by
a) hydrogenation using a catalyst containing palladium, platinum, rbodium or nickel in a suitable solvent e.g. acetic acid or ethanol at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or
b) debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd/C and at a reaction temperature between +20xc2x0 C. and reflux.
3.
(i) Conversion of the compound of formula (XXXI) described in Sunkyung L.; Stewart P. F.; David E. N. Synth. Commun. 1995, 25(18), 2775-2780, where the protected ketone may be protected as other ketals, cyclic or acyclic, or by other protective groups known by a person skilled in the art (see T. W. Greene, Wiley-Interscience, New York, 1991), to a compound of formula (XXXII) 
where R1 is C1-C6 alkyl or C3-C6 cycloalkyl, may be carried out by the reaction with a compound of formula (XVII). 
The process may be carried out in a suitable solvent e.g. an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N,N-dimethylformamide with a suitable base such as sodium tert-butoxide or lithium bis(trimethylsilyl)amide in the presence of a suitable palladium catalyst such as PdX2, L2Pd(0) or L2PdX2 where X stands for a halogen such as chlorine or bromine and L stands for a suitable ligand such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, triphenylarsine or dibenzylidenacetone and with or without an addition of a ligand Lxe2x80x2 such as triphenylphosphine, tri-o-tolylphosphine, trifulrylphosphine, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthalene (either as a racemate or as an enantiomer) or triphenylarsine and the reaction may occur at a temperature between 20xc2x0 C. and +150xc2x0 C., resulting in the compound of the formula (XXXII).
The conversion of (XXXI) to (XXXII) can also proceed via the tranformation of (XVII) to an aminostannane or aminoborane using agents such as (N,N-diethylamino)tributyltin and tris(dimethylamino)borane in a suitable solvent e.g an aprotic solvent such as benzene, toluene, dioxan, tetrahydrofuran or N,N-dimethylformamride and then using similar conditions as described in the above description, resulting in a compound of the formula (XXXII). 
(ii) Conversion of a compound of formula (XXXII) to a compound of formula (XXXIII) may be carried out by using a suitable aqueous acid such as HCl, HBr or acetic acid at a reaction temperature between +20xc2x0 C. and reflux or by other methods known by a person skilled in the art (see T. W. Greene, Wiley-Interscience, New York, 1991). 
The above reaction is followed by the conversion of the ketone of the formula (XXXIII) to compound of formula (XXXIV) by the reaction with an appropriate cyanation reagent such as tosylmethyl isocyanide in the presence of suitable base e.g. potassium tert-butoxide in a suitable solvent such as 1,2-dimethoxyethane, dimethyl sulfoxide or hexamethylphosphoric triamide containing small amounts of an alcohol such as methanol, ethanol or tert-butanol at a temperature between 0xc2x0 C. and +100xc2x0 C. or via cyanohydrin formation and then conversion to a compound of formula (XXXIV). 
(iii) Hydrolysis of a compound of formula (XXXIV) to a compound (XXXV) may be carried out under acidic conditions using acids such as H2SO4, HCl, HBr, in a suitable solvent such as H2O, ethanol, methanol, acetic acid or mixtures thereof and the reaction may occur at a temperature between +20xc2x0 C. and reflux or under basic conditions using bases such as NaOH or KOH in a suitable solvent such as H2O, ethanol, methanol or mixtures thereof at a temperature between +20xc2x0 C. and reflux.
4.
i) Nitration of a compound of formula (XXXVI), described in Johnson D. W.; Mander L. N. Aust. J. Chem 1974, 27,1277-1286, either as racemate or as an enantiomer, to obtain a compound of formula (XXXVII), 
where Re is C1-C6 alkyl, may be carried out by aromatic electrophilic substitution using a suitable nitration reagent such as nitric acid or nitric acid and sulfuric acid in a suitable solvent e.g. acetic acid, acetic anhydride or water at a reaction temperature between xe2x88x9220xc2x0 C. and room temperature.
(ii) Demethylation of the compound of the formula (XXXVII) to obtain a compound of formula (XXXVIII) 
may be carried out by treating the compound with an acidic reagent such as aqueous HBr, HI, HBr/CH3COOH, BBr3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as CH3C6H4Sxe2x88x92 or C2H5Sxe2x88x92. Suitable solvents may be methylene chloride or chloroform and the reaction may occur between xe2x88x9278xc2x0 C. and +60xc2x0 C.
During the demethylation of (XXXVII), hydrolysis of the ester may occur and the acid function could then be converted back to the ester by methods known by a person skilled in the art (See T. W. Greene, Wiley-Interscience, New York, 1991).
(iii) Conversion of the compound of formula (XXXVIII) to a compound of formula (XXXIX) 
may be carried out by the reaction with an activated trifluoromethanesulfonic reagent e.g. trifluoromethanesulfonic anhydride in a suitable solvent such as methylene chloride, chloroform or carbon tetrachloride in the presence of a suitable base such as triethylamine, pyridine or 2,4,6-collidine at a reaction temperature between xe2x88x9278xc2x0 C. and room temperature.
(iv) Conversion of the compound of formula (XXXIX) to a compound of formula (XL) may be carried out by 
a) hydrogenation using a catalyst containing palladium, platinum or nickel in a suitable solvent such as ethanol, methanol or acetic acid and at a reaction temperature between +20xc2x0 C. and +120xc2x0 C. or
b) reaction in a suitable solvent such as methanol in the presence of a ammonium formate such as triethyl ammonium formate and Pd/C and at a reaction temperature between +20xc2x0 C. and reflux.
(v) Conversion of the compound of formula (XL) to a compound of formula (XLI) 
may be carried out by reaction of compound (XI) 
where X stands for a leaving group, e.g. a halogen such as chlorine or bromine or an alkane- or arenesulfonyloxy group such as p-toluene-sulfonyloxy group and R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl. The process may be carried out in a suitable solvent such as ethanol, buthanol, N,N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base e.g. K2CO3, NaHCO3 or KOH and the reaction may occur between +20xc2x0 C. and +150xc2x0 C. During the cyclization reaction of (XL), hydrolysis of the ester may occur. 
(vi) Hydrolysis of a compound of formula (XLI) may be carried out under acidic conditions using acids such as H2SO4, HCl, HBr, in a suitable solvent such as H2O, ethanol, methanol, acetic acid or mixtures thereof at a temperature between +20xc2x0 C. and reflux or under basic conditions using bases such as NaOH or KOH in a suitable solvent such as as H2O, ethanol, methanol or mixtures thereof at a temperature between +20xc2x0 C. and reflux, resulting in a compound of formula (XXXV), where R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl.
(vii) When R1 is hydrogen, protection of a compound of formula (XXXV) as a compound of formula (XLII) where Rd is a protecting group 
may be carried out by the reaction with a suitable protecting reagent such as di-tert-butyl dicarbonate in a suitable solvent e.g methylene chloride or chloroform with a suitable base such as triethylamine or K2CO3 and at a temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C.
5. 
(i) Conversion of a compound of formula (XII), where R1 is C1-C6 alkyl or C3-C6 cycloalkyl, to a compound of formula (XLIII) may be carried out by the alkylation of compound of formula (XII) with a suitable alkylation reagent such as R2xe2x80x94Z where Z is a suitable leaving group e.g. a halogen such as chlorine, bromine or iodine or an alkane- or arenesulfonyloxy group such as p-toluenesulfonyloxy group and R2 is C1-C6 alkyl. The reaction may be carried out in a suitable solvent such as N,N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran with a suitable base such as K2CO3, NaHCO3, NaOH or a trialkylamine such as triethylamine. The reaction may be conducted at a temperature between +20xc2x0 C. and +120xc2x0 C.
(ii) In the case where R2 is methyl, conversion of compound of formula (XII) to a compound of formula (XLIII) may be carried out by 
a) conversion of the compound of formula (XII) to a compound of formula (XLIV), where R1 is C1-C6 alkyl or C3-C6 cycloalkyl and Re is C1-C6 alkyl, with a reagent such as an alkyl chloroformate e.g. ethyl chloroformate in a solvent such as methylene chloride, chloroform, dioxane or diethyl ether with a suitable base such as K2CO3, NaHCO3, NaOH or a trialkylamine such as triethylamine at a reaction temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C. followed by,
b) reduction of compound of formula (XLIV) to a compound of formula (XLIII) with an appropriate reductive agent such as lithium aluminum hydride in a suitable solvent e.g. diethyl ether or tetrahydrofiran at a temperature between +20xc2x0 C. and reflux.
Methods of Preparation of End Products
Method A(i): 
Acylation of the compound of formula (XII) wherein X is N or (XXVIIII) wherein X is CH and R1 is C1-C6 alkyl or C3-C6 cycloalkyl, may be carried out with an appropriate activated is carboxylic acid, R3xe2x80x94COL where R3 is as defined in claim 1 and L is a leaving group such as a halogen e.g. chlorine, in a suitable solvent such as methylene chloride or chloroform with a suitable base e.g. trialkylamine such as triethylamine at a temperature between xe2x88x9220xc2x0 C. and reflux temperature or by using a carboxylic acid, R3xe2x80x94COOH, where R3 is as defined in claim 1 with an activating reagent e.g. N,Nxe2x80x2-carbonyldiimidazole or N,Nxe2x80x2-dicyclohexylcarbodiimide in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran and the reaction may be conducted at a temperature between +20xc2x0 C. and +150xc2x0 C., resulting in the compound of the formula (I) according to the invention, wherein Y is NR2CO, where R2 is hydrogen, and X is N or CH and R1 is C1-C6 alkyl or C3-C6 cloalkyl, and R3 is as in claim 1.
Method A(ii): 
Acylation of the compound of formula (XIVa), wherein X is N or CH and Rd is a protecting group,may be carried out with an appropriate activated carboxylic acid R3xe2x80x94COL, where R3 is as defined in claim 1 and L is a leaving group such as a halogen e.g. chlorine, in a suitable solvent such as methylene chloride or chloroform with a suitable base e.g. trialkyl amine such as triethylamine at a temperature between xe2x88x9220xc2x0 C. and reflux temperature or by using a carboxylic acid, R3xe2x80x94COOH, where R3 is as defined in claim 1 with an activating reagent e.g. N,Nxe2x80x2-carbonyldiimidazole or N,Nxe2x80x2-dicyclohexylcarbodiimide in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran at a temperature between +20xc2x0 C. and +150xc2x0 C., followed by removal of the protecting group Rd by hydrolyzis in a suitable solvent such as methylene chloride or chloroform with a suitable acid such as trifluoroacetic acid at a temperature between +20xc2x0 C. and +60xc2x0 C., resulting in a compound of the formula (I) according to the invention, wherein Y is NR2CO, R1 and R2 are hydrogen, X and R3 are as in claim 1.
Method A(iii) 
Acylation of the compound of formula (XLIIIa), wherein X is N or CH, R1 is C1-C6 alkyl or C3-C6 cycloalkyl, R2 is C1-C6 alkyl may be carried out with an appropriate activated carboxylic acid R3xe2x80x94COL, where R3 is as defined in claim 1 and L is a leaving group such as a halogen e.g. chlorine, in a suitable solvent such as methylene chloride or chloroform with a suitable base e.g. trialkyl amine such as triethylamine at a temperature between xe2x88x9220xc2x0 C. and reflux temperature by using a carboxylic acid, R3xe2x80x94COOH, where R3 is as defined in claim 1 or by using an activating reagent e.g. N,Nxe2x80x2-carbonyldiimidazole or N,Nxe2x80x2-dicyclohexylcarbodiirnide in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran at a temperature between +20xc2x0 C. and +150xc2x0 C., resulting in a compound of the formula (I) according to the invention, wherein Y is NR2CO, R2 is C1-C6 alkyl, R1 is C1-C6 alkyl or C3-C6 cycloalkyl and X and R3 are as in claim 1.
Method B(i) 
Conversion of a compound of formula (XXXVa), wherein X is N or CH and R1 is C1-C6 alkyl or C3-C6 cycloalkyl, to a compound of formula (I) according to the invention, wherein Y is CONR2, R2 is hydrogen or C1-C6 alkyl, R1 is C1-C6 alkyl or C3-C6 cycloalkyl and X and R3 are as in claim 1, may be carried out by activation of the acid function of a compound of formula (XXXVa) as an acid halide such as an acid chloride or by using an activating reagent such as N,Nxe2x80x2-carbonyldiimidazole or N,N-dicyclohexylcarbodiimide in a suitable solvent e.g. methylene chloride, chloroform, toluene, N,N-dimethylformamide, dioxane or tetrahydrofuran followed by the addition of an appropriate amine or aniline HNR2R3 and the reaction may occur between 0xc2x0 C. and +120xc2x0 C.
Method B(ii) 
Conversion of a compound of formula (XLIIa), wherein X is N or CH and Rd is a protecting group, to a compound of formula (I) according to the invention, wherein Y is CONR2, R2 is hydrogen or C1-C6 alkyl, R1 is hydrogen and X and R3 are as in claim 1, may be carried out by activation of the acid function of a compound of formula (XLIIa) as an acid halide such as an acid chloride or by using an activating reagent such as N,Nxe2x80x2-carbonyldimidazole or N,N-dicyclohexylcarbodiimide in a suitable solvent e.g. methylene chloride, chloroform, toluene, N,N-dimethylformamide, dioxane or tetrahydrofuran followed by the addition of an appropriate amine or aniline HNR2R3 and the reaction may occur between 0xc2x0 C. and +120xc2x0 C., followed by removal of the protecting group Rd by methods known by a person skilled in the art such as hydrolysis in a suitable solvent such as methylene chloride or chloroform with a suitable acid e.g. trifluoroacetic acid at a temperature between +20xc2x0 C. and +60xc2x0 C.
Method C 
Conversion of a compound of formula (XIIa), wherein X is N or CH and R1 is C1-C6 alkyl or C3-C6 cycloalkyl, to a compound of formula (I) according to the invention, wherein Y is NR2SO2, R2 is hydrogen, R1 is C1-C6 alkyl or C3-C6 cycloalkyl and X and R3 are as in claim 1, may be carried out by reaction with an appropriate activated sulfonic acid R3SO2L, where L is a leaving group such as a halogen e.g. a chlorine in a suitable solvent such as methylene chloride or chloroform with a suitable base e.g. trialkyl amine such as triethylamine and the reaction may be conducted at a temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C.
Method D(i) 
Reduction of a compound of formula (I), according to the invention wherein X is N or CH, Y is NR2CO, R2 is hydrogen or C1-C6 alkyl, R1 is hydrogen, C1-C6 alkyl or C3-C6 cloalkyl and X and R3 are as in claim 1 (above denoted (Ia)) obtained by method A(i), A(ii) or A(iii) above, to a compound of formula (I) according to the invention where Y is NR2CH2 and X, R1, R2 and R3 are as defined above (above denoted (Ib)) may be carried out with an appropriate reductive agent such as lithium aluminum hydride in a suitable solvent e.g. diethyl ether or tetrahydrofuran at a temperature between +20xc2x0 C. and reflux temperature.
Method D(ii) 
Reduction of a compound of formula (I) according to the invention wherein X is N or CH, Y is CONR2, R2 is hydrogen or C1-C6 alkyl, R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl and X and R3 are as in claim 1, (above denoted (Ic)) and obtained by method B(i) or B(ii) above, to a compound of formula (I) according to the invention wherein Y is CH2NR2, X, R1, R2 and R3 are as defined in claim 1 (above denoted (Id)) may be carried out with an appropriate reductive agent such as lithium aluminum hydride in a suitable solvent e.g. diethyl ether or tetrahydrofuran at a temperature between +20xc2x0 C. and reflux temperature.
Method E 
Alkylation of compound of formula (XIIa), wherein X is N or CH, R1 is C1-C6 alkyl or C3-C6 cycloalkyl, R2 is hydrogen, or a compound of formula (XIVa), wherein X is N or CH, R1 is Rd, where Rd is a protecting group, and R2 is hydrogen, or a compound of formula (XLIIIa), wherein X is N or CH, R1 is C1-C6 alkyl or C3-C6 cycloalkyl and R2 is C1-C6 alkyl to a compound of formula (I), according to the invention, wherein Y is NR2CH2, X, R1 and R2 are as above, and R3 is as in claim 1 may be carried out with a suitable alkylation reagent such as R3CH2xe2x80x94L, where L is a suitable leaving group e.g. a halogen such as chlorine, bromine or iodine or an alkyl- or arylsulfonyloxy group such as p-toluene sulfonyloxy group. The reaction may be carried out in a suitable solvent such as N,N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran with a suitable, base such as K2CO3, NaHCO3, NaOH or a trialkylamine such as triethylamine. The reaction may be conducted at a temperature between +20xc2x0 C. and +120xc2x0 C. In the case when R1 is Rd, the alkylation is followed by removal of the protecting group Rd by hydrolysis in a suitable solvent such as methylene chloride or chloroform with a suitable acid such as trifluoroacetic acid at a temperature between +20xc2x0 C. and +60xc2x0 C.
Method F 
Alkylation of a compound of formula (Ie), according to the invention wherein X is N or CH, Y is NR2CO, R2 is hydrogen or C1-C6 alkyl and R3 is as in claim 1, and obtained by method A(ii), to a compound of formula (If) according to the invention wherein Y is NR2CO, R2 is hydrogen or C1-C6 alkyl, R1 is C1-C6 alkyl and X and R3 are as in claim 1 may be carried out with a suitable alkylation reagent such as R1xe2x80x94L where L is a suitable leaving group e.g. a halogen such as chlorine, bromine or iodine or an alkyl- or arylsulfonyloxy group such as p-toluenesulfonyloxy group and R1 is C1-C6 alkyl. The reaction may be carried out in a suitable solvent such as N,N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran with a suitable base such as K2CO3, NaHCO3, NaOH or a trialkylamine such as triethylamine. The reaction may be conducted at a temperature between +20xc2x0 C. and +120xc2x0 C.
Intermediates
The present invention also refers to new intermediates, namely intermediates of formula 
wherein
Z=NH2 or COOH,
X=CH or N, and
R1=H, C1-C6 alkyl or C3-C6 cycloalkyl.